Intracellular phosphorylation events have a decisive impact on the longterm outcome of various pathological conditions by modulating the survival of cells subjected to genetic or environmental insults. In particular, inappropriate activation of certain kinases critically involved in the regulation of the cell cycle, or in the case of postmitotic cells like neurons, in the maintenance of the respective differentiation states, can undermine beneficial physiological responses to a pathological challenge, like apoptosis of cancer cells or neuronal recovery under metabolic stress.
It has become appreciated that certain key kinases, like those belonging to the cell cycle regulated or MAP-kinase superfamilies, are ubiquitously expressed but perform fundamentally different functions in different biological contexts. In proliferating cell types, the physiological activation of such kinases tends to exert a dominant control over cell proliferation, either by synchronizing intracellular events (cdks) or by integrating environmental stimuli and intercellular signals (MAP-kinases). Therefore, intervention on the level of such kinases has therapeutic utility in a variety of cancers.
The involvement of the key MAP-kinase ERK2 and several members of the cdk family in cancer biology is amply documented. Constitutively activated ERK1/2 proteins are a frequent abnormality, e.g., in melanoma cells, often caused by mutation of a membrane receptor coupled to the ERK signal transduction pathways [Abi-Habib et al., Mol. Cancer. Ther. 4, 1303-1310 (2005); Takata et al., J. Invest. Dermatol. 125, 318-322 (2005)]. For most tumor cells with this abnormality, inhibition of the ERK-pathway is toxic. Constitutively activating receptor mutations are a common theme in tumor biology, and a large number of such receptors feed into the ERK pathway. One of the widely known examples are mutations in the signaling molecule ras upstream of the ERK cascade, which account for a sizeable fraction of cancers across the spectrum of originating tissues. Prominent in breast cancer are mutations in the ERB family of tyrosine kinase receptors. However, Tykerb, a new agent used for treatment of Herceptin resistant tumors, shows growth inhibitory activity only in about 20% of a large panel of breast cancer tumor cell lines, in spite of having dual specificity for two ERB receptor subtypes [Konecny et al., Cancer Res. 66, 1630-1639 (2006)]. In contrast, all of the cell lines tested had some level of constitutive ERK2 activity. Thus, intervention on the level of ERK, however, should provide for a more universal therapeutic principle than targeting a myriad of sometimes still unknown upstream receptors with oncogenic mutations [e.g., Zuidervaart et al., Br. J. Cancer 92, 2032-2038 (2005)]. De novo or emerging resistance to other more specific intervention strategies [e.g., Gee et al., Endocr. Relat. Cancer 12 Suppl., S99-S111 (2005)] may also be much less of a problem at the level of ERK2: the homology of ERK2 across mammalian species is virtually absolute, indicating either the absence of mutagenic activity in the respective gene, or a lack of tolerance for any alterations of the protein. Clinical utility of specific interference with ERK activity has recently been demonstrated in patients with advanced malignancies by treatment with an inhibitor of the only known upstream activating kinase of ERKs, termed MEK1/2, thus acting as a proxy for inhibition of ERKs [Lorusso et al., J. Clin. Oncol. 23, 5281-5293 (2005)]. However, even with the clearly very central role of the MAP-kinase pathway in tumor cell transformation, surprising limitations of efficacy of highly specific inhibitors of MEK1/2, and thereby ERK2, have become apparent. While such inhibitors are quite effective in raf-transformed cells, they were shown to loose efficacy in tumor cells harboring oncogenic ras-mutations [Solit et al., Nature 439, 358-362 (2006)], where apparently another pathway besides the MAP-kinase cascade is utilized to provide sufficient transforming activity. This is particularly serious in view of the fact that more than 50% of all known tumors include oncogenic mutations of Ras, thereby providing ample opportunity for unpredictable efficacy or emergence of resistance in recurrent tumors.
There is an urgent need for more broadly acting inhibitors, addressing the ERK pathway, but also preventing the by-pass observed in a majority of clinical cancers. Such inhibitors should finally show the broad therapeutic utility in cancers presenting a broad spectrum of molecular oncogenic mechanisms, and thereby affect the clinically most important outcome of patient survival.